This project is directed at delineating the pathogenic mechanisms of human immunodeficiency virus (HIV) infection and the role of immune activation in the propagation of disease and destruction of the immune system. We have previously demonstrated that HIV infects the human thymus in the SCID-hu mouse and leads to depletion of thymocytes and destruction of the microenvironment. Treatment of SCID-hu mice with cyclosporin A blocks infection of the thymus, and this inhibition appears related to a decrease in cellular activation. Activation of the human immune system in vivo appears to accelerate the course of HIV disease. We demonstrate that, after tetanus toxoid booster inoculation of HIV- infected individuals, HIV can be more readily isolated from their peripheral blood mononuclear cells (PBMCs) in vitro and plasma viremia increases over 2 to 3 weeks. The degree of increase in in vitro virus expression and viremia appears to correlate somewhat with total CD4 lymphocyte count and also with the ability of the individual to respond immunologically to the tetanus boost; thus the more immunologically intact HIV-infected individuals mount a more appropriate immune response to tetanus and thereby experience a more dramatic increase in viremia and in vitro isolation of HIV from their PBMCs. HIV seronegative individuals become more susceptible to in vitro infection of their PBMCs with HIV after tetanus toxoid booster immunization. This heightened susceptibility to in vitro infection occurs at the time that the individual is making a vigorous response to tetanus as assessed by PBMC proliferation to tetanus in vitro and production of tetanus specific immunoglobulin.